Combined Silymarin and Cotrimoxazole Therapy Attenuates Pulmonary Fibrosis in Experimental Paracoccidioidomycosis

Abstract

Paracoccidioidomycosis (PCM), which mainly affects rural workers, is a systemic mycosis caused by the Paracoccidioides genus that induces pulmonary sequelae in most adult patients, causing serious disability and impairing their quality of life. Silymarin is herbal medicine with an effective antifibrotic activity. Considering that in PCM, antifibrotic treatment is still not available in pulmonary fibrosis, we aimed to evaluate combined silymarin and cotrimoxazole (CMX) therapy via the intratracheal route in BALB/c mice infected with P. brasiliensis yeast. After 12 weeks of treatment, the lungs were collected for the determination of fungal burden, production of OH-proline, deposition of collagen fibers, pulmonary concentrations of cytokines, and expression of fibronectin, α-SMA, MMP-2, MMP-9, and TIMP-2. Spleen cell cultures were also performed. Our results showed that infected mice treated with combined silymarin/CMX showed lower deposition of collagen fibers in the lungs and lower pulmonary concentrations of hydroxyproline than the placebo groups. Decreased levels of TGF-β1 and fibronectin and high levels of MMP-2 and IFN-γ were also observed in this group of mice. Collectively, our findings indicate that the combination of antifungal treatment with silymarin has a potent antifibrotic effect associated with an immunomodulatory effect that potentializes the antifungal immune response.

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“…Inhibited MMP-2 and IFN-γ. [ [79] , [80] , [81] , [82] ] Dihydromyricetin C 15 H 12 O 8 Ampelopsis grossedentata In vivo: BLM-induced male C57BL/6 mice (50, 100 mg/kg). In vitro: Primary mouse lung fibroblasts, Primary human lung fibroblasts (100 μM, 200 μM, 300 μM).…”

“…Silymarin exhibited a remarkable influence on pulmonary fibrosis, as evidenced by reduced deposition of collagen fibers and diminished pulmonary concentrations of hydroxyproline. Furthermore, significant alterations were observed in key molecular markers, with decreased levels of TGF-β1, fibronectin, and elevated levels of MMP-2 and IFN-γ [ 82 ].…”

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“…Silymarin decreases lung hydroxyproline concentrations and collagen fiber deposition, which have a substantial impact on pulmonary fibrosis. In addition, silymarin significantly altered the levels of key molecular markers, including decreased levels of TGF-β1 and fibronectin and increased levels of matrix metallopeptidase 2 (MMP-2) and IFN-γ [174]. Calycosin enhanced the expression of the Nrf2/HO-1 signaling pathway and induced apoptosis, and significantly inhibited bleomycin(BLM)-induced inflammation and collagen deposition in mice.…”